Lipid-conjugated Heteroduplex oligonucleotide administration for ischemic stroke in the hyperacute phase

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07733
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Satoru Ishibashi 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (30533369)
• Co-Investigator(Kenkyū-buntansha): 石黒 太郎 東京医科歯科大学, 医学部附属病院, 助教 (20748587)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 脳血管障害 / 核酸医薬 / 動物モデル / 薬剤送達

Outline of Final Research Achievements

Antisense oligonucleotide (ASO) is a major tool used for silencing pathogenic genes. For stroke in the hyperacute stage, however, the ability of ASO to regulate genes is limited by its poor delivery to the ischemic brain owing to sudden occlusion of the supplying artery. Here we show that, in a mouse model of permanent ischemic stroke, lipid-ligand conjugated DNA/RNA heteroduplex oligonucleotide (lipid-HDO) was unexpectedly delivered 9.6 times more efficiently to the ischemic area of the brain than to the contralateral non-ischemic brain and achieved robust gene knockdown and change of stroke phenotype. This delivery to neurons was mediated via receptor-mediated transcytosis by lipoprotein receptors in brain endothelial cells, the expression of which was significantly upregulated after ischemia. This study provides proof-of-concept that lipid-HDO is a promising gene-silencing technology for stroke treatment in the hyperacute stage.

Free Research Field

脳血管障害

Academic Significance and Societal Importance of the Research Achievements

脳梗塞後の病態や治療標的となる遺伝子は解明されつつあるも、急性期に投与可能な有効な薬剤開発が実現できていない。脳血流の減少やBBBによるバリア機能により、脳梗塞病変への薬剤送達が困難なことが課題であった。脂質ライガンド結合HDO技術は、この課題を克服することができ脳梗塞急性期治療の遺伝子制御ツールとして臨床応用されることが期待される。我々の技術は、経静脈的投与により投与が可能であることは合併症予防の観点からも非常に優れているといえる。